Melatonin, represented by the structure below: ##STR1##
is named systematically as N-[2-(5-methoxy-3-indolyl)ethyl]-acetamide. Trivial names for the compound include N-acetyl-5-methoxytryptamine and N-acetyl-O-methylserotonin. Melatonin is a pineal gland hormone which has ovulation inhibitory activity, Chu et al., Endocrinology, 75, 238 (1964), as well as some activity against MCF-7 human breast cancer cells, Blask et al. J. Neural. Transm. [Supp.], 21, 433 (1986) and for the treatment of mammalian breast carcinoma, Blask et al., Neuroendocrinol. Lett., 9(2), 63 (1987). Furthermore, melatonin has been known to expedite recovery from "jet lag syndrome", Arendt et al., Ergonomics, 30, 1379 (1987), to cause sleep, Waldhauser et al., Psychopharmacology, 100, 222 (1990) and to minimize disturbances in circadian rhythms of bodily performance and function, U.S. Pat. Nos. 4,600,723 and 5,242,941.
Several melatonin analogues of the formula ##STR2##
wherein
R.sup.1 is hydrogen, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy; PA1 R.sup.2 is hydrogen or C.sub.1 -C.sub.4 alkyl; PA1 R.sup.3 is hydrogen or methyl; PA1 R.sup.4 is hydrogen, haloacetyl, C.sub.1 -C.sub.5 alkanoyl, benzoyl or benzoyl substituted with halo or methyl; PA1 R.sup.5 and R.sup.6 are individually hydrogen or halo; and PA1 R.sup.7 is hydrogen or C.sub.1 -C.sub.4 alkyl; PA1 provided that when R.sup.2 is hydrogen, at least one of R.sup.5 and R.sup.6 is halo, have also been prepared and shown to possess ovulation inhibition activity (see U.S. Pat. Nos. 4,997,845 and 4,614,807). Such analogues are also stated to be active in treating hormonally dependent breast carcinomas in U.S. Pat. No. 5,196,435. However, none of these analogues were previously shown to possess activity in treating desynchronization disorders. PA1 R.sup.1 is hydrogen, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy; PA1 R.sup.2 is hydrogen or C.sub.1 -C.sub.4 alkyl; PA1 R.sup.3 is hydrogen, C.sub.1 -C.sub.4 alkyl, phenyl or substituted phenyl; PA1 R.sup.4 is hydrogen, haloacetyl, C.sub.1 -C.sub.5 alkanoyl, benzoyl or benzoyl substituted with halo or methyl; PA1 R.sup.5 and R.sup.6 are each individually hydrogen or halo; and PA1 R.sup.7 is hydrogen or C.sub.1 -C.sub.4 alkyl; PA1 provided that when R.sup.2 is hydrogen then at least one of R.sup.5 and R.sup.6 is halo.
Finally, European Patent Application 513,702 discloses that melatonin and its analogues of the formula ##STR3##
wherein R.sup.1 and R.sup.2 are the same or different and are hydrogen or halogen can be used in treating sleep disorders and in pre-anesthetic medication. Again, such disclosure does not teach or suggest the use of melatonin analogues for treating desychronization disorders.
It is an object of this invention to provide a method for treating desynchronization disorders by employing certain melatonin analogues. The instant method is believed to provide a more efficacious (in terms of activity, side effect profile and duration of action) means for treating such disorders than previously known. Further, the melatonin analogues used in the instant method are believed to be completely devoid of toxicity at the dosages required for treatment and, as such, a further object of the present invention is to provide a safe, efficacious, method of treating desynchronization disorders. Other objects, features and advantages of the present invention will become apparent from the subsequent description and the appended claims.